Patients with metastatic urothelial carcinoma (mUC) are typically elderly and often have other comorbidities that require the use of concomitant medications. In our study we evaluated the association of concomitant use of antibiotics (ATBs), proton pump inhibitors (PPIs), corticosteroids, statins, metformin and insulin with patient outcomes and we validated the prognostic role of a concomitant drug score in mUC patients treated with enfortumab vedotin (EV) monotherapy. Data from 436 patients enrolled in the ARON-2EV retrospective study were analyzed according to the concomitant medications used at baseline. Finally, the patients were stratified into three risk groups according to the concomitant drug score based on ATBs, corticosteroids and PPIs. Statistical analysis involved Fisher exact test, Kaplan-Meier method, log-rank test, and univariate/multivariate Cox proportional hazard regression models. Inferior survival outcomes were observed in ATB users compared to non-users (OS: 7.3 months, 95%CI 5.0 - 12.3 vs 13.7 months, 95%CI 12.2 - 47.3, p = 0.001; PFS: 5.1 months 95%CI 3.3 - 17.7 vs 8.3 months, 95%CI 7.1 - 47.3, p = 0.001) and also in corticosteroid users compared to non-users (OS: 8.4 months, 95%CI 6.6 - 10.0 vs 14.2 months, 95%CI 12.7 - 47.3, p < 0.001; PFS: 6.0 months 95%CI 4.6 - 7.9 vs 8.9 months, 95%CI 7.2 - 47.3, p = 0.004). In the Cox multivariate analysis, the concomitant drug score was a significant factor predicting both OS (HR = 1.32 [95% CI 1.03 - 1.68], p = 0.026) and PFS (HR = 1.23 [95% CI 1.01 - 1.51], p = 0.044). Our findings suggest detrimental impact of concomitant use of ATBs and corticosteroids on survival outcomes and the prognostic utility of the concomitant drug score in previously treated mUC patients receiving EV.

Biomedical Center Faculty of Medicine in Pilsen Charles University Pilsen Czech Republic

Clinical Oncology Genitourinary Oncology Unit Alexander Fleming Institute Buenos Aires Argentina

Department of Comprehensive Cancer Care Faculty of Medicine Masaryk University 625 00 Brno Czech Republic

Department of Comprehensive Cancer Care Masaryk Memorial Cancer Institute 656 53 Brno Czech Republic

Department of Hemato Oncology Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran Escuela de Medicina Mexico Universidad Panamericana Mexico City Mexico

Department of Medical and Surgical Sciences University of Bologna Bologna Italy

Department of Medical Oncology Ankara University Faculty of Medicine 06620 Ankara Türkiye

Department of Medical Oncology Azienda Ospedaliera Universitaria Maggiore Della Carit Novara Italy

Department of Medical Oncology Cliniques Universitaires Saint Luc Brussels Belgium

Department of Medical Oncology Complejo Hospitalario Universitario Insular Materno Infantil Las Palmas Spain

Department of Medical Oncology Hospital Ramón y Cajal Madrid Spain

Department of Medical Oncology Koc University Medical Faculty Istanbul Türkiye

Department of Medicine and Surgery University of Parma Parma Italy

Department of Oncology 2nd Faculty of Medicine Charles University and Motol University Hospital 5 Úvalu 84 150 06 Prague Czech Republic

Department of Oncology and Radiotherapeutics Faculty of Medicine and University Hospital in Pilsen Charles University Prague Alej Svobody 80 304 60 Pilsen Czech Republic

Department of Oncology Faculty of Medicine and Dentistry Palacký University Olomouc Czech Republic

Department of Oncology University Hospital in Hradec Králové Sokolská 581 50005 Hradec Králové Czech Republic

Department of Uro Oncology Maria Sklodowska Curie National Research Institute of Oncology Warsaw Warsaw Poland

Department of Urology Kindai University Faculty of Medicine Osaka Japan

Department of Urology Saitama Medical Center Saitama Medical University Saitama Japan

Department of Urology The Jikei University School of Medicine 3 19 18 Nishi Shimbashi Minato Ku Tokyo 105 8471 Japan

Dipartimento di Oncologia Ospedale Michele E Pietro Ferrero Verduno ASLCN2 Alba E Bra Italy

Hospital Israelita Albert Einstein São Paulo SP Brazil

Hospital Sírio Libanês Brasília DF Brazil

Latin American Cooperative Oncology Group LACOG Porto Alegre Brazil

Medical Oncology 1 IRCCS Regina Elena National Cancer Institute Rome Italy

Medical Oncology Department Fondazione IRCCS Istituto Nazionale Dei Tumori Via Giacomo Venezian 1 Milan Italy

Medical Oncology IRCCS Azienda Ospedaliero Universitaria Di Bologna Bologna Italy

Medical Oncology Unit Macerata Hospital Macerata Italy

Medical Oncology Unit University Hospital of Parma Parma Italy

Samsung Medical Center Sungkyunkwan University School of Medicine Seoul Korea

Section of Innovation Biomedicine Oncology Area Department of Engineering for Innovation Medicine of Verona 37134 Verona Italy

Taussig Cancer Institute Cleveland Clinic Cleveland OH USA

U O Oncologia Ospedale Di Civitanova Marche Civitanova Marche Italy

Unit of Medical Oncology and Biomolecular Therapy Department of Medical and Surgical Sciences University of Foggia Policlinico Riuniti Foggia Italy

Zobrazit více v PubMed

Mohanty SK, Lobo A, Cheng L (2023) The 2022 revision of the World Health Organization classification of tumors of the urinary system and male genital organs: advances and challenges. Human Pathol 1(136):123–143 PubMed

Domb C, Garcia JA, Barata PC, Mendiratta P, Rao S, Brown JR (2024) Systematic review of recent advancements in antibody-drug and bicycle toxin conjugates for the treatment of urothelial cancer. Ther Adv Urol. 10.1177/17562872241249073 PubMed PMC

Powles T, Rosenberg JE, Sonpavde GP, Loriot Y, Durán I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Wu C, Campbell M, Matsangou M, Petrylak DP (2021) Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med 384(12):1125–1135. 10.1056/NEJMoa2035807 PubMed PMC

Rosenberg JE, Powles T, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Mamtani R, Wu C, Matsangou M, Campbell M, Petrylak DP (2023) EV-301 long-term outcomes: 24-month findings from the phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated advanced urothelial carcinoma. Ann Oncol 34(11):1047–1054. 10.1016/j.annonc.2023.08.016 PubMed

Powles T, Bellmunt J, Comperat E, De Santis M, Huddart R, Loriot Y, Necchi A, Valderrama BP, Ravaud A, Shariat SF, Szabados B, van der Heijden MS, Gillessen S, ESMO Guidelines Committee (2024) ESMO clinical practice guideline interim update on first-line therapy in advanced urothelial carcinoma. Ann Oncol 35(6):485–490. 10.1016/j.annonc.2024.03.001 PubMed

Pinato DJ, Howlett S, Ottaviani D, Urus H, Patel A, Mineo T, Brock C, Power D, Hatcher O, Falconer A, Ingle M, Brown A, Gujral D, Partridge S, Sarwar N, Gonzalez M, Bendle M, Lewanski C, Newsom-Davis T, Allara E, Bower M (2019) Association of prior antibiotic treatment with survival and response to immune checkpoint inhibitor therapy in patients with cancer. JAMA Oncol 5(12):1774–1778 PubMed PMC

Hopkins AM, Kichenadasse G, Karapetis CS, Rowland A, Sorich MJ (2020) Concomitant antibiotic use and survival in urothelial carcinoma treated with atezolizumab. Eur Urol 78(4):540–543. 10.1016/j.eururo.2020.06.061 PubMed

Fukuokaya W, Kimura T, Komura K, Uchimoto T, Nishimura K, Yanagisawa T et al (2022) Effectiveness of pembrolizumab in patients with urothelial carcinoma receiving proton pump inhibitors. Urol Oncol 40(7):346.e1-346.e8. 10.1016/j.urolonc.2022.02.020 PubMed

Tomisaki I, Harada M, Minato A, Nagata Y, Kimuro R, Higashijima K et al (2022) Impact of the use of proton pump inhibitors on pembrolizumab effectiveness for advanced urothelial carcinoma. Anticancer Res 42(3):1629–1634. 10.21873/anticanres.15638 PubMed

Okuyama Y, Hatakeyama S, Numakura K, Narita T, Tanaka T, Miura Y et al (2021) Prognostic impact of proton pump inhibitors for immunotherapy in advanced urothelial carcinoma. BJUI Compass 3:154–161. 10.1002/bco2.118 PubMed PMC

Rizzo A, Santoni M, Mollica V, Ricci AD, Calabrò C, Cusmai A et al (2022) The impact of concomitant proton pump inhibitors on immunotherapy efficacy among patients with urothelial carcinoma: a meta-analysis. J Pers Med 12(5):842. 10.3390/jpm12050842 PubMed PMC

Fiala O, Buti S, Takeshita H, Okada Y, Massari F, Palacios GA et al (2023) Use of concomitant proton pump inhibitors, statins or metformin in patients treated with pembrolizumab for metastatic urothelial carcinoma: data from the ARON-2 retrospective study. Cancer Immunol Immunother 72(11):3665–3682. 10.1007/s00262-023-03518-z PubMed PMC

Maslov DV, Tawagi K, Kc M, Simenson V, Yuan H, Parent C, Bamnolker A, Goel R, Blake Z, Matrana MR, Johnson DH (2021) Timing of steroid initiation and response rates to immune checkpoint inhibitors in metastatic cancer. J Immunother Cancer 9(7):e002261. 10.1136/jitc-2020-002261 PubMed PMC

Bruera S, Suarez-Almazor ME (2022) The effects of glucocorticoids and immunosuppressants on cancer outcomes in checkpoint inhibitor therapy. Front Oncol 23(12):928390. 10.3389/fonc.2022.928390 PubMed PMC

Buti S, Bersanelli M, Perrone F et al (2021) Effect of concomitant medications with immune-Modulatory properties on the outcomes of patients with advanced cancer treated with immune checkpoint inhibitors: development and validation of a novel prognostic index. Eur J Cancer 142:18–28 PubMed

Buti S, Bersanelli M, Perrone F et al (2021) Predictive ability of a drug-based score in patients with advanced non-small-cell lung cancer receiving first-line Immunotherapy. Eur J Cancer 150:224–231 PubMed

Takada K, Buti S, Bersanelli M et al (2022) Antibiotic-dependent effect of probiotics in patients with non-small cell lung cancer treated with PD-1 checkpoint blockade. Eur J Cancer 172:199–208 PubMed

Buti S, Basso U, Giannarelli D et al (2023) Concomitant drugs Prognostic score in patients with metastatic renal cell carcinoma receiving Ipilimumab and Nivolumab in the compassionate use program in Italy: brief communication. J Immunother 46:22–26 PubMed PMC

Taguchi S, Kawai T, Buti S et al (2023) Validation of a drug-based score in advanced urothelial carcinoma treated with Pembrolizumab. Immunotherapy 15:827–837 PubMed

Schwartz LH, Litière S, de Vries E, Ford R, Gwyther S, Mandrekar S et al (2016) RECIST 1.1-update and clarification: from the RECIST committee. Eur J Cancer 62:132–137. 10.1016/j.ejca.2016.03.081 PubMed PMC

Kraynov E, Kamath AV, Walles M, Tarcsa E, Deslandes A, Iyer RA et al (2016) Current approaches for absorption, distribution, metabolism, and excretion characterization of antibody-drug conjugates: an industry white paper. Drug Metab Dispos 44(5):617–623 PubMed

Chen Y, Wang X, Ye Y et al (2024) Gut microbiota in cancer: insights on microbial metabolites and therapeutic strategies. Med Oncol 41:25. 10.1007/s12032-023-02249-6 PubMed

Gopalakrishnan V, Helmink BA, Spencer CN, Reuben A, Wargo JA (2018) The influence of the gut microbiome on cancer, immunity, and cancer immunotherapy. Cancer Cell 33(4):570–580. 10.1016/j.ccell.2018.03.015.PMID:29634945;PMCID:PMC6529202 PubMed PMC

Cheng WY, Wu CY, Yu J (2020) The role of gut microbiota in cancer treatment: friend or foe? Gut 69(10):1867–1876. 10.1136/gutjnl-2020-321153 PubMed PMC

Becattini S, Taur Y, Pamer EG (2016) Antibiotic-induced changes in the intestinal microbiota and disease. Trends Mol Med 22(6):458–478. 10.1016/j.molmed.2016.04.003 PubMed PMC

Jernberg C et al (2007) Long-term ecological impacts of antibiotic administration on the human intestinal microbiota. ISME J 1:56–66. 10.1038/ismej.2007.3 PubMed

Reddy M, Kader K (2018) Follow-up management of cystectomy patients. Urol Clin North Am 45(2):241–247. 10.1016/j.ucl.2018.01.001 PubMed

Linehan J, Schoenberg M, Seltzer E, Thacker K, Smith AB (2021) Complications associated with ureteroscopic management of upper tract urothelial carcinoma. Urology 147:87–95. 10.1016/j.urology.2020.09.036 PubMed

Seto CT, Jeraldo P, Orenstein R, Chia N, DiBaise JK (2014) Prolonged use of a proton pump inhibitor reduces microbial diversity: implications for Clostridium difficile susceptibility. Microbiome 2:42. 10.1186/2049-2618-2-42 PubMed PMC

Clooney AG, Bernstein CN, Leslie WD, Vagianos K, Sargent M, Laserna-Mendieta EJ et al (2016) A comparison of the gut microbiome between long-term users and non-users of proton pump inhibitors. Aliment Pharmacol Ther 43(9):974–984. 10.1111/apt.13568 PubMed

Imhann F, Bonder MJ, Vich Vila A, Fu J, Mujagic Z, Vork L et al (2016) Proton pump inhibitors affect the gut microbiome. Gut 65(5):740–748. 10.1136/gutjnl-2015-310376 PubMed PMC

Freedberg DE, Lebwohl B, Abrams JA (2014) The impact of proton pump inhibitors on the human gastrointestinal microbiome. Clin Lab Med 34(4):771–785. 10.1016/j.cll.2014.08.008 PubMed PMC

Wu T, Yang L, Jiang J, Ni Y, Zhu J, Zheng X, Wang Q, Lu X, Fu Z (2018) Chronic glucocorticoid treatment induced circadian clock disorder leads to lipid metabolism and gut microbiota alterations in rats. Life Sci 1(192):173–182. 10.1016/j.lfs.2017.11.049 PubMed

Lee RT, Ramchandran K, Sanft T, Von Roenn J (2015) Implementation of supportive care and best supportive care interventions in clinical trials enrolling patients with cancer. Ann Oncol 26(9):1838–1845. 10.1093/annonc/mdv207 PubMed

Chan KK, Oza AM, Siu LL (2003) The statins as anticancer agents. Clin Cancer Res 9:10–19 PubMed

Keyomarsi K, Sandoval L, Band V (2003) Synchronization of tumor and normal cells from G1 to multiple cell cycles by lovastatin. Cancer Res 9:10–19 PubMed

Wong WW, Dimitroulakos J, Minden MD, Penn LZ (2002) HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis. Leukemia 16:508–519 PubMed

Samuel SM, Varghese E, Kubatka P, Triggle CR, Büsselberg D et al (2019) Metformin: the answer to cancer in a flower? current knowledge and future prospects of metformin as an anti-cancer agent in breast cancer. Biomolecules 9(12):846. 10.3390/biom9120846 PubMed PMC

Chen YC, Li H, Wang J (2020) Mechanisms of metformin inhibiting cancer invasion and migration. Am J Transl Res 12(9):4885–4901 PubMed PMC

Ferro M, Marchioni M, Lucarelli G, Vartolomei MD, Soria F, Terracciano D et al (2021) Association of statin use and oncological outcomes in patients with first diagnosis of T1 high grade non-muscle invasive urothelial bladder cancer: results from a multicenter study. Minerva Urol Nephrol 73(6):796–802. 10.23736/S2724-6051.20.04076-X PubMed

Haimerl L, Strobach D, Mannell H, Stief CG, Buchner A, Karl A et al (2022) Retrospective evaluation of the impact of non-oncologic chronic drug therapy on the survival in patients with bladder cancer. Int J Clin Pharm 44(2):339–347. 10.1007/s11096-021-01343-x PubMed PMC

Søndergaard CS, Esquivel PN, Dalamaga M, Magkos F (2023) Use of antihyperglycemic drugs and risk of cancer in patients with diabetes. Curr Oncol Rep 25(1):29–40. 10.1007/s11912-022-01344-7 PubMed

Farhan SY et al (2009) The use of insulin and the effect on survival of non-small cell lung cancer patients. JCO 27:e22073–e22073. 10.1200/jco.2009.27.15_suppl.e22073

Ioacara S, Guja C, Ionescu-Tirgoviste C, Fica S, Roden M (2014) Cancer specific mortality in insulin-treated type 2 diabetes patients. PLoS ONE 9:e93132. 10.1371/journal.pone.0093132 PubMed PMC

Baglia ML, Cui Y, Zheng T, Yang G, Li H, You M, Xu L, Murff H, Gao YT, Zheng W, Xiang YB, Shu XO (2019) Diabetes medication use in association with survival among patients of breast, colorectal, lung, or gastric cancer. Cancer Res Treat 51(2):538–546. 10.4143/crt.2017.591 PubMed PMC